Fibroblast growth factor 21 (FGF21) is a potent endocrine regulator with physiological effects on glucose and lipid metabolism and thus garners much attention on its translational potential for the management of obesity and related metabolic syndromes. FGF21 is mainly expressed in several metabolically active tissue organs, such as the liver, adipose tissue, skeletal muscle and pancreas with profound effects and therapeutically relevance. Emerging experimental and clinical data point to the demonstrated metabolic benefits of FGF21 which includes, but not limit to, weight loss, glucose and lipid metabolism as well as insulin sensitivity. Besides, FGF21 also acts directly through its co-receptor β-klotho in the brain to alter light-dark cycle activity. In this review, we critically appraise the current advance in the physiological actions of FGF21 and its role as a biomarker of various metabolic diseases, especially type 2 diabetes mellitus (T2DM). We also discuss the potential exciting role of FGF21 in improving our health and prolonging our life span. This information will provide a fuller understanding for further researches into FGF21, as well as providing a scientific basis for potential establishing a healthcare guideline of this promising molecule.